Traumatic brain injury (TBI) in humans as an incredibly heterogeneous disease and the significant effort involved in developing and characterizing reproducible and clinically-relevant models of specific types of TBI has enabled the neurotrauma research community to begin to identify important and injury-specific mechanisms of cell death and dysfunction. This application revolves around the general hypotheses that selective molecular and cellular pathways are activated or initiated which are injury-specific mechanisms of cell death and are activated or initiated which are injury-specific. Through the sue of selective experimental models that closely simulate the major classes of human TBI, we can better understand and characterize the pathological sequelae of clinical head injury and explore novel mechanistic-based therapies. We have chosen to focus on several exciting areas, including (1) the relationship between TBI and the cellular events associated with Alzheimer's and other neurodegenerative disease, (2) the role of the dysfunctional cytoskeleton and calpain-mediated cytoskeletal proteolysis in post- traumatic neuronal death and damage, and (3) the activation of cell death enzymes such as MAP kinases and caspases and their role in post- traumatic cell death. We will continue to forge mechanistic links between these pathological cascades and outcome following TBI. We will also evaluate (4) the important role of secondary hypoxia/ischemia in the exacerbation of cellular injury and the association with one or more of the pathologic mechanisms studied in these Projects. Finally, we will use the accumulated molecular and cellular information to design and drive novel neuroprotective strategies to enhance recovery of function and attenuate neuronal cell death. These projects will be significantly supported by human/histopathology, biomechanics, molecular biology, and administrative cores. We believe that the understanding of the specific cellular and molecular mechanisms underlying cell death and dysfunction is critically important to the continuation of scientific progress in this field and to the development of novel therapeutic strategies targeted to treat human brain injury.